Mescaline,among the earliest identified natural hallucinogens,holds great potential in psychotherapy treatment.Nonetheless,despite the existence of a postulated biosynthetic pathway for more than half a century,the sp...Mescaline,among the earliest identified natural hallucinogens,holds great potential in psychotherapy treatment.Nonetheless,despite the existence of a postulated biosynthetic pathway for more than half a century,the specific enzymes involved in this process are yet to be identified.In this study,we investigated the cactus Lophophora williamsii(Peyote),the largest known natural producer of the phenethylamine mescaline.We employed a multi-faceted approach,combining de novo whole-genome and transcriptome sequencing with comprehensive chemical profiling,enzymatic assays,molecular modeling,and pathway engineering for pathway elucidation.We identified four groups of enzymes responsible for the six catalytic steps in the mescaline biosynthetic pathway,and an N-methyltransferase enzyme that N-methylates all phenethylamine intermediates,likely modulating mescaline levels in Peyote.Finally,we reconstructed the mescaline biosynthetic pathway in both Nicotiana benthamiana plants and yeast cells,providing novel insights into several challenges hindering complete heterologous mescaline production.Taken together,our study opens up avenues for exploration of sustainable production approaches and responsible utilization of mescaline,safeguarding this valuable natural resource for future generations.展开更多
Dear Editor,In T-cell acute lymphoblastic leukemia(T-ALL),an aggressive hematologic cancer with poor clinical outcomes,more than 50%of cases show NOTCH1-driven transformation[1].The NOTCH1 receptor signaling pathway i...Dear Editor,In T-cell acute lymphoblastic leukemia(T-ALL),an aggressive hematologic cancer with poor clinical outcomes,more than 50%of cases show NOTCH1-driven transformation[1].The NOTCH1 receptor signaling pathway is activated through a series of proteolytic cleavages,ultimately causing the release of the active intracellular domain(NICD),which translocates to the nucleus where it promotes transcription of target genes involved in cell growth.The importance of NOTCH1 mutations in T-ALL has generated great interest in the development of anti-NOTCH1 targeted therapies.A new and promising emerging field in cancer treatment is medical cannabis.Accumulating evidence suggests the direct effects of cannabis on tumor progression in cell lines and animal models[2].Cannabis,and its unique secondary metabolites,known as phytocannabinoids,directly affect the propagation of cancer cells by modulating key cellsignaling pathways[3].We have previously demonstrated that different cannabis extracts,each containing a unique composition of metabolites,selectively impaired the survival of cancer cell lines depending on amatch between the chemical composition of the extract and the characteristics of the specific cancer cell line[4].In the present work,we set out to investigate whether cannabis extracts with unique phytocannabinoid profiles can selectively facilitate antitumor effects in T-ALL cells that harbor a Notch1 mutation.展开更多
基金fellowships from the Israel Ministry of Absorption and the Dean of the Plant Science Department in the Weizmann Institute.We thank Prof.David Nelson(University of Tennessee,USA)for the systematic naming of the cytochrome P450 enzymes characterized in this studyShmuel Regev and The Regev Nursery(Beit Elazari,Israel)for help in differentiating among Lophophora species+2 种基金Dr.Ziv Spiegelman for providing several N.benthamiana plantsXINTEZA(https://xinteza.com/)for funding this researchand the Adelis Foundation,the Leona M.and Harry B.Helmsley Charitable Trust,the Jeanne and Joseph Nissim Foundation for Life Sciences,Tom and Sondra Rykoff Family Foundation Research,Ron Sklare and the Raymond Burton Plant Genome Research Fund for supporting the A.A.laboratory。
文摘Mescaline,among the earliest identified natural hallucinogens,holds great potential in psychotherapy treatment.Nonetheless,despite the existence of a postulated biosynthetic pathway for more than half a century,the specific enzymes involved in this process are yet to be identified.In this study,we investigated the cactus Lophophora williamsii(Peyote),the largest known natural producer of the phenethylamine mescaline.We employed a multi-faceted approach,combining de novo whole-genome and transcriptome sequencing with comprehensive chemical profiling,enzymatic assays,molecular modeling,and pathway engineering for pathway elucidation.We identified four groups of enzymes responsible for the six catalytic steps in the mescaline biosynthetic pathway,and an N-methyltransferase enzyme that N-methylates all phenethylamine intermediates,likely modulating mescaline levels in Peyote.Finally,we reconstructed the mescaline biosynthetic pathway in both Nicotiana benthamiana plants and yeast cells,providing novel insights into several challenges hindering complete heterologous mescaline production.Taken together,our study opens up avenues for exploration of sustainable production approaches and responsible utilization of mescaline,safeguarding this valuable natural resource for future generations.
文摘Dear Editor,In T-cell acute lymphoblastic leukemia(T-ALL),an aggressive hematologic cancer with poor clinical outcomes,more than 50%of cases show NOTCH1-driven transformation[1].The NOTCH1 receptor signaling pathway is activated through a series of proteolytic cleavages,ultimately causing the release of the active intracellular domain(NICD),which translocates to the nucleus where it promotes transcription of target genes involved in cell growth.The importance of NOTCH1 mutations in T-ALL has generated great interest in the development of anti-NOTCH1 targeted therapies.A new and promising emerging field in cancer treatment is medical cannabis.Accumulating evidence suggests the direct effects of cannabis on tumor progression in cell lines and animal models[2].Cannabis,and its unique secondary metabolites,known as phytocannabinoids,directly affect the propagation of cancer cells by modulating key cellsignaling pathways[3].We have previously demonstrated that different cannabis extracts,each containing a unique composition of metabolites,selectively impaired the survival of cancer cell lines depending on amatch between the chemical composition of the extract and the characteristics of the specific cancer cell line[4].In the present work,we set out to investigate whether cannabis extracts with unique phytocannabinoid profiles can selectively facilitate antitumor effects in T-ALL cells that harbor a Notch1 mutation.
